We have shown that p53 promotes aerobic metabolism through its positive regulation of mitochondrial respiration. p53 null mice, a model of de novo tumorigenesis, display profound deficiencies in aerobic exercise capacity. Remarkably, the promotion of exercise capacity by a tumor suppressor gene in a mouse model parallels the human epidemiologic observation of a strong inverse relationship between exercise capacity and cancer incidence. We hypothesize that these two independent observations may share common mechanisms for tumor suppression, therefore, we are investigating the regulation of mitochondrial function by p53 using in vitro and in vivo models. We are focusing on cardiovascular and metabolic functions in individuals with Li-Fraumeni syndrome, a premature cancer syndrome caused by germline mutations in the p53 gene. The goal of this work is to derive insights from human studies that may assist in the development of new strategies for preventing cancer and improving cardiovascular health.